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This is a newsletter for the International Severe Acute Respiratory and emerging Infection Consortium
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ISARIC News

Issue 1, 2015
In this issue:
Chair's Message | Update from ISARIC CC | GloPID-r-Sec Update | Ebola trials: RAPIDE Platform | Ebola Convalescent Blood and Plasma Studies | SPRINT-SARI | Data solutions for epidemic response | PREPARE Update | USCIIT-PREP | InFACT Winter 2015 Meeting
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Chair's Message


This year has continued the theme begun over a year ago in March 2014 with the initiation of the Ebola outbreak in West Africa of learning to walk whilst running for ISARIC. As such, ISARIC have succeeded brilliantly in core areas of its mission to respond to global outbreaks, as evidenced by reports in this issue of the newsletter, whilst having to defer important areas of its growth and development as a global network. On the one hand, ISARIC have won important new competitive opportunities, such as its partnership with Fondation Merieux in forming the Secretariat for GLOPID-r, fostered new research, as well as additional core funding for the Coordinating Centre from the Medical Research Council (UK), Wellcome Trust and the Bill & Melinda Gates Foundation; whilst on the other we have had to delay the important goal of expanding membership from networks in low and middle income countries in Asia and Sub-Saharan Africa, as well as restructuring the Vice Chairs and successfully holding elections. Much of this is captured in this issue of the newsletter.
 
Each of these experiences, both the successes as well as the setbacks have taught us valuable lessons about not how better to balance our responses to the demands placed on ISARIC, but how better to anticipate and acquire some of many resources ISARIC need in order to successfully pursue its core objectives.
 
In the immediate coming weeks, the Executive Committee will be discussing each of the remaining unfulfilled objectives, including membership expansion in low and middle income countries and internal restructuring, both of which we anticipate will further strengthen our capacity. In the meantime, our accomplishments to date give us much to leave us optimistic about ISARIC’s future.
 
Thank you very much for continuing to support ISARIC.
 
Best wishes,
 
W. Abdullah Brooks
ISARIC Chair

Update from ISARIC CC

- Gail Carson, Kajsa-Stina Longuere, Raul Pardinaz-Solis & Sarah Moore

The Coordinating Centre has been very busy supporting the Ebola treatment trials in West Africa, kicking off the GloPID-r-secretariat project, and otherwise supporting ISARIC activities - some of which are described further in this newsletter. Keeping the Coordinating Centre running in an ongoing outbreak situation has proven challenging but fully possible, thanks to the commitment and efforts put in by, for instance, Sarah Moore, who joined the ISARIC CC as an extra pair of hands and at very short notice in November (thank you Sarah!). We are currently mapping out the potential challenges faced and met, which we hope will feed into an Operational Plan that will come to life during future outbreaks, that is being written up under Mike Christian's leadership.

The ISARIC CC will continue to support the Ebola studies that fall under ISARIC's umbrella, but to a lesser extent as the projects now rely less on our help. Our upcoming activities will instead focus more towards the tasks outlined in the Glopid-r-sec proposal as befalling the ISARIC CC (UOXF) this includes repeating our capabilities and capacities survey, kicking off a study into the true burden of influenza under Fred Hayden's leadership (supported by the Gates Foundation), support the continuous global roll out of the Clinical Characterisation Protocol as previously communicated, building the ISARIC membership base in Low and Middle Income Countries further, and support grant applications for regional "PREPAREs" in Africa and Asia, amongst many other tasks. Further communication about all of these activities will be sent continuously, and members are encouraged to send any queries related to the activities of the Coordinating Centre directly to Kajsa by email.

Finally, as what was left of our seed funding came to an end in 2013 and 2014, another great challenge for the CC has been to secure the necessary funding to keep ISARIC running for the next couple of years. We are delighted to report that we have managed to secure renewed funds from the Bill and Melinda Gates Foundation, Medical Research Council UK, and the Wellcome Trust, which  - in addition to the contribution towards salary costs that the Glopid-r-Sec grant from the European Commission entails, will see ISARIC's Coordinating Centre funded until the end of 2017. We would like to take this opportunity to thank all funders for their continued support for ISARIC and our objectives.

GloPID-r-Sec Update

- Menno de Jong & ISARIC CC

Under the leadership of Menno de Jong, ISARIC’s Coordinating Centre through the University of Oxford, is partnering with Fondation Merieux in forming the GloPID-r Secretariat, which is an European Commission funded proposal under the Horizon 2020 programme. The Secretariat aims to support funders that have signed up to GloPID-r in developing a coordinated strategic agenda that will enable a global and coordinated funders’ response to an outbreak situation. The overall coordination and main secretarial duties lay with Fondation Merieux under the leadership of Hubert Endtz, while ISARIC CC is leading two work packages through Gail Carson (WP2) and Peter Horby (WP3).

WP2 is seeking to map the capacity and capability of funders and existing research networks including animal health and social sciences as well as the political, economic, regulatory, logistic, ethical, and social barriers (PERLES) that face them in an outbreak situation, or in preparation for pandemic responses. The WP2 work is done in collaboration with Al Nichol (ICCTG), who is leading on similar work within PREPARE (see below) and within ISARIC's WG4. The WP2 team is currently preparing to send out surveys to research networks (including the ISARIC membership) and funders as a part of the mapping effort of capacities, capabilities, outbreak readiness and PERLES barriers within both the research community and among funders globally. Preparations are also being made for an Ebola Case Study which will particularly look into the global Ebola response through a series of interviews with both funders and researchers.

Supported by WP2's work and outcomes, WP3 is supporting the development of a strategic agenda for GloPID-r. All ISARIC’s GloPID-r-Sec activities overlap and feed into other on-going ISARIC activities and projects.
Team discussion, Port Loko, Sierra Leone.
Photo: Raul Pardinaz-Solis

Ebola trials: RAPIDE Platform

- Peter Horby (ERGO, University of Oxford)

As part of the broader RAPIDE trial platform, RAPIDE-TKM is a Wellcome Trust funded phase II study of TKM-Ebola treatment in Sierra Leone that is led by Peter Horby on ISARIC’s behalf. Run in partnership with the Sierra Leone College of Medicine and Allied Health Sciences, the Sierra Leone Ministry of Health, the WHO-based Special Programme for Research and Training in Tropical Diseases, the UK Department for International Development, Public Health England, and GOAL Global, this is a single-arm study that aims to investigate the efficacy of TKM-Ebola-Guinea, a synthetic small interfering RNA (siRNA) therapeutic designed specifically to target the strain of virus that is causing the current Ebola outbreak. The first results are expected in the second half of 2015. The RAPIDE platform also ran a brincidofovir (BCV) trial in Liberia, and is supporting the convalescent plasma trial currently running in Sierra Leone (see below).

Press release
Link to Ebola Trials website – RAPIDE-TKM

Ebola Convalescent Blood and Plasma Studies in West Africa.

- Calum Semple (FLU-CIN)

The first convalescent plasma was donated by Sierra Leonia survivors of Ebola in Freetown on Thursday (14h of April). A representative for the Sierra Leone Association of Ebola Survivors, Ahmed Wurrie Barrie (photo) was one of the first to donate plasma, saying "I survived Ebola for many reasons, donating plasma to save more lives might just be one of them."

Of the three West African countries affected by Ebola, Sierra Leone has so far had the greatest number of cases (8563) and deaths (3491)  [Confirmed cases per WHO Sit Rep 15APR2015]. This country is similar in size and population to my Scotland with 5.7 million souls but in contrast ‘Salone’ had only 50 or so practicing doctors before the Ebola outbreak. At least eleven of them have died of Ebola.
 
One of the prêt-à-porter study protocols developed by ISARIC members was for a trial of convalescent plasma. Led initially by Gernot Rohde (CAPNETZ) and working closely with colleagues in WHO the protocol was first refined for use in the Middle East Respiratory Syndrome Coronavirus (MERS-CoV). Louise Sigfrid, Kenny Baillie, others and I worked on adapting it for use in viral haemorrhagic fever. When Johan van Griensven of the Institute of Tropical Medicine Antwerp was applying to the Wellcome Trust to fund an Ebola convalescent blood and plasma study, his application was brought to the attention of ISARIC for potential support and collaboration. The ISARIC convalescent blood and plasma protocol was adapted for his application and ISARIC members were listed on he application.
 
Johan’s study in Guinea (Ebola_Tx) is going well: as of this week 92 subjects have been enrolled; 89 have been transfused. The youngest to receive a plasma transfusion is three months old.
 
In November WHO asked Kenny Baillie, Anke Kohlenberg (ITM Antwerp) and me to advise Sierra Leonean investigators on rapidly establishing a Convalescent Blood and Plasma study. Of the three affected countries, Sierra Leone faces some of the greatest challenges in infrastructure. Our advice was that the local team press ahead with a compassionate use of convalescent whole blood in an open observational study without delay, which they did. However it was agreed that the development of a convalescent plasma study, with all the technical challenges that plasma apheresis entails, should be done with international partnership and in close collaboration with Johan’s study in Guinea. Johan’s team agreed to share the study protocol and data management system.

The Sierra Leone study (Ebola_CP) was dependent in part upon use of apheresis machines that had been sourced by a Sierra Leonean diaspora, however local political problems meant this resource was lost in December. Meanwhile the study of convalescent plasma in Liberia (EVD001) led by David Hoover of ClinicalRM with Duke University and University of North Carolina had run out of patients. Consistent with the ISARIC principles, the PIs of Ebola_Tx, Ebola_CP and EVD001 had already shared protocols and added endpoints to ensure data aggregation across the three studies. Trust had been established. One additional discussion led to ClinicalRM agreeing to collaborate in Sierra Leone providing apheresis technology, training, clinical trials support and monitoring.
 
Janet Scott (Liverpool) is our clinical lead on Ebola_CP, she also previously worked as a RAPIDE team member, in both Liberia and Sierra Leone. Very complementary about working and collaborating with the teams at the 34th Regiment Military Hospital and the Blood Service at the Connaught Hospital, Janet and the team were delighted to receive the first donations of plasma this week. While we have missed giving CP to what we hope was the last wave of this outbreak, we will be able to characterise the convalescent donor’s humoral profiles and generate a bank of good quality plasma ready for a recrudescence or future outbreak.
 
The ISARIC Coordinating Centre in Oxford has been a huge asset. The team led by Gail Carson facilitated our rapid deployment and then provided logistical and welfare back-up. I was able to use the office to route essential time sensitive equipment (thanks Jake) and anti-malarial tablets to deployed staff (thanks Clare). While writing this piece I was asked to source support for the local laboratory. One call to the ISARIC office gave me access to people on standby ready to work in the field to support our research. This role for the ISARIC office was perhaps one not initially planned when ISARIC was established, but its value must be recognised and retained for future outbreaks.

See Calum's presentation on Ebola CP

Short Period Incidence Study of Severe Acute Respiratory Infection (SPRINT SARI)

- Steve Webb & Genevieve O'Neill (ANZICS)

SPRINT-SARI is an ambitious project hoping to better characterize Severe Acute Respiratory Infections (SARI) around the globe to better inform management strategies and ultimately to improve the ability of health care systems to rapidly respond to emerging infections. SARI continues to be of major relevance to public health. In the last 10 years there have been multiple SARI outbreaks around the world, as witnessed with the H1N1, H7N9, H5N1, SARS, and MERS-CoV outbreaks.  The 2009 H1N1 pandemic was estimated to result in more than 200,000 respiratory deaths globally. Seasonal flu is estimated to result in severe illness in between 3-5 million cases and 250,000-500,000 deaths annually.
 
SPRINT-SARI primarily aims to investigate the feasibility of conducting a global observational study of SARI and to establish global capacity to perform observational research in a variety of settings for pandemic research preparedness. The secondary aims of this study are to investigate the descriptive epidemiology and microbiology profiles of patients with SARI around the world and collect information to facilitate extrapolation from data collected at hospital level to the whole-of-population level (including but not limited to, global / local incidence and burden, global treatment variances, the relationship between co-morbidity and outcome).
 
SPRINT-SARI is a multi-network, multicentre, prospective, short period incidence observational study of all SARI patients admitted to the in-patient unit of interest at participating hospital during a defined 5-7day study period.  The study will be conducted in as many locations as possible, in a variety of in-patient departments, based on Network and hospital research infrastructure. The case definition of SARI will be slightly adapted from current WHO definitions to better understand the operational characteristics and consequences of different components in alternative SARI case definitions. 
 
Due to the variation in clinical and research infrastructure at participating sites, SPRINT-SARI will use an adapted WHO and ISARIC SARI Natural History and Biological Sampling case record forms (CRF). A tiered data collection approach will provide sites with the opportunity to choose which of the four data collection tiers they complete, according to their own objectives and abilities. SPRINT-SARI will explicitly aim to provide local junior and emerging investigators with the opportunity to spearhead local collaboration and an opportunity to increase their research capabilities. 
 
In the event of a respiratory epidemic or pandemic, participating hospitals will have the ability to immediately conduct clinical research with SPRINT-SARI’s existing research infrastructure, and ethical, administrative, and regulatory approvals.  This research will provide pivotal and timely information on the severity of the pandemic and its impact on the provision of healthcare services globally.  
 
The study is currently in the developmental phase, EOI’s will be sent to requesting Networks to participate in June 2015. It is proposed to study patients admitted in the northern hemisphere winter (2015/2016), the southern hemisphere winter (2016), and tropical regions in-between these times. The study coordinator is Genevieve O’Neill who can be contacted directly by email here.

Data solutions for epidemic response

-Laura Merson (OUCRU)

In order to achieve the goal to change the paradigm of emerging infections research, ISARIC members are collaborating with the World Health Organisation to harmonise data systems, standardise outcome measures and provide data tools to support research in outbreaks. 
 
Since 2012, ISARIC and WHO have collaborated on data solutions for severe acute respiratory illness (SARI).  The results of widespread consultation on scientific and operational priorities for SARI outbreaks include a set of standardised case report forms and an associated data capture system.  Both are open access for anyone to download, alter and use.  The forms are designed to capture data on all types of SARI, regardless of whether the cause is unknown, emerging, re-emerging or endemic.  The forms have a tiered structure which allow sites to determine how much data they will collect based on their available resources.  The forms and data systems are now in use in dozens of countries for a myriad of studies including retrospective and prospective studies of MERS-Coronavirus in Saudi Arabia, exploring unknown causes of SARI in Viet Nam and determining the spectrum of SARI in Singapore, Australia and North America. 
 
In June 2014, ISARIC began work with the WHO to address the need for data on the Ebolavirus disease outbreak in West Africa.  Evidence was urgently needed to refine case definitions and clinical guidance documents as well as to inform public health policy.  Data was challenging to collect and extract from the treatment units, therefore an informed evaluation of data priorities was needed.  Supported by dozens of experts in the field, a modified Delphi method was rapidly undertaken to determine the most critical data variables needed to promote high quality care and improve outcomes.  A set of data collection forms was developed, with variables prioritised into scalable tiers allowing flexibility according to the level of resources available.  The forms were distributed to the organisations building ETUs in West Africa, and to clinical trials groups developing protocols.      
 
In order to support high-quality, clinically-relevant science, ISARIC members convened forums for discussion on harmonising data definitions and outcomes in EVD therapeutic trials.  Data tools, including a dictionary named and structured according to the Clinical Data Interchange Standards Consortium (CDISC) was made available to support data management efforts of all trial teams, avoid duplication of effort, and enable rapid pooling of datasets to strengthen power.  This work continues toward the development of a Therapeutic Area Standard, which will define the data requirements for the registration of EVD therapies.   
 
Efforts to maximize the scientific output of the available EVD data continue via collaboration of the data holders on plans for a data-sharing platform.  Pooling the large volumes of data now available will strengthen power to understand the pathophysiology of the disease and analyse the effectiveness of different treatment and operational strategies.  Harmonization of EVD survivor data, now in progress by ISARIC, WHO, and many survivor clinics, will facilitate the collection of robust evidence on EVD sequelae and support those caring for survivors.
 
For information on these and other ISARIC data efforts, please contact Laura directly by email here.
 

PREPARE Update

WP1 – Alistair Nichol (ICCTG)
 
The EARL group consists of researchers from University College Dublin, Cardiff University and the University of Western Australia. We are trying to identify solutions to conducting clinical research during a future pandemic.
 
We have examined the processes necessary for trial approval in the 26 EU member states, interviewed researchers and clinicians in many EU member states.  We will be publically disseminating our first detailed report shortly.
 
In addition, we are finalising a review of different consent processes used in critically ill patients.  We will conduct a number of surveys and focus groups to determine the opinions of European citizens regarding consent models and novel trial designs that PREPARE will adopt during a future pandemic.
 
On a more global stage through ISARIC WG4 we are co-ordinating these efforts with PREPARE-Australia and other ISARIC members to conduct aspects of these studies globally.
 
 
WP2 – Peter Horby (ERGO, University of Oxford)
 
The PRIME Work Package aims to solve clinical obstacles to the rapid conduct of clinical trials. A survey will be sent out to network leads across Europe in order to assess usage and availability of case definitions and clinical management guidelines for five syndromes (CNS, respiratory, diarrhoeal, haemorrhage fever, sepsis in infants). The team is conducting a systematic review of guidelines for the hospital management of community acquired lower respiratory tract infections and central nervous system infections, with the objective to identify differences that may affect the conduct of research during epidemics of these syndromes.
 
WP3 – Peter Horby (ERGO, University of Oxford)
 
As part of the PRACTICE clinical trials stream in PREPARE, PRACTICE A aims to deliver large-scale prospective observational studies of infections with epidemic potential in Europe under the banner: Multicentre EuRopean study of Major Infectious Disease Syndromes (MERMAIDS). The WP3 team has surveyed paediatric sites across Europe as part of a pilot study, and has produced three draft MERMAIDS protocols: 1) Arboviral compatible febrile illness; 2) Community-acquired sepsis-like syndrome in infants; 3) Pathogenesis of Acute Respiratory Infections.
 
WP5 – Derek Angus (CRISMA) & Steve Webb (ANZICS CTG)
 
As part of PREPARE, WP5 focuses on the design, launch and execution of a novel clinical trial program to determine optimal strategies for the care of patients with severe acute respiratory infections. The program is based on an adaptive trial ‘platform’ that will test alternative anti-infective, host immunomodulation and mechanical ventilation strategies simultaneously. The novel design features include embedding the clinical trial inside existing ICU clinical protocols, testing many different strategies simultaneously, and generating estimates of treatment effect for different subgroups of patients. The program begins with a pilot project, which already has ethical approval, and which had the investigator launch meeting this week in Brussels. The main project is on track to launch in the next 18 months. Of particular note, this program, with the flexibility to test multiple different treatment strategies, is particularly suited to incorporate new arms during epidemics of novel infections causing severe respiratory failure. Finally, the program is also designed to integrate with similar efforts for which funding is being sought in Australasia and North America.
 
WP6 – Menno de Jong (Amsterdam Medical Center)
 
PATHOS – the pathogenesis Work Package has conducted systematic reviews on genetic host susceptibility and on host gene expression profiling during acute respiratory infections which provided direction for the design of the SARI part of the MERMAIDS (see WP3 above) protocol. The team is also producing infra-and microarray platforms that will be expanded to include next generation RNA sequencing methods, and a knowledge management platform on ARI, including data and text mining tools.
 
Parts of this article are based on the latest PREPARE newsletter, please see the full newsletter here

More information about all of the PREPARE Work Packages can be found on the PREPARE website here.

North American Cooperative for Emergency Preparedness

- J. Perren Cobb (USCIITG)

To address national strategic vulnerabilities for real-time patient-level data aggregation, analysis, and reporting, the North American Cooperative for Emergency Preparedness was created in 2014 with funding to the United States Critical Illness and Injury Trials Group Program for Emergency Preparedness (USCIIT-PREP) from the Association of Public Health Laboratories (APHL) and the Centers for Disease Control (CDC).  The aims of the Cooperative are to 1) create a framework for preparedness that facilitates multinational collaboration and data sharing among the dominant clinical research networks in North America (U.S, Canada, and Mexico), and maintain harmonization with the research endpoints and data sharing platform of the international research networks for acute care, critical illness, and injury, and 2) standardize data elements for electronic case report forms (eCRF), establishing a consensus approach to the design of clinical protocols and preparing templates for development of locally-appropriate studies that are pre-approved by institutional research board (IRB) in advance of outbreaks of severe acute respiratory infection (SARI) and other emerging infections and public health emergencies.  Collaborating organizations include the Canadian Critical Care Trials Group (CCCTG), International Forum for Acute Care Trialists (InFACT), International Network for Strategic Initiatives in Global HIV Trials (INSIGHT), International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), Mexican Emerging Infectious Disease Clinical Research Network (La RED), and USCIIT-PREP.  To address the aims of the Cooperative, face-to-face meetings were held at the annual gatherings of USCIIT (Bethesda, MD, USA, November 2014) and the International Forum for Acute Care Trialists (see InFACT above).  Results of the meetings and recommendations moving forward are being prepared; a synopsis will be provided in an next edition of this newsletter.

International Forum for Acute Care Trialists (InFACT) Winter 2015 Meeting

 - John Marshall (InFACT)

More than 50 people affiliated with member groups of InFACT and ISARIC met for three days in Lake Louise in the Canadian Rocky Mountains at the end of April.   The meeting followed on the winter meeting of the Canadian Critical Care Trials Group, and addressed 8 separate themes through small working groups - Developing a Canadian PREPARE application, developing the SPRINT SARI study, building an InFACT outcome measures working group, harmonizing and sharing research tools, mapping global capacity for acute care, understanding the structure and processes of investigator-led clinical trials groups, mentoring and developing emerging research groups and building a North American pandemic preparedness capacity.   We were joined by representatives from the Canadian Institutes of Health Research and the Public Health Agency of Canada.  Terrific progress was made on all fronts, aided and abetted in no small part by a spectacular environment, superb skiing, and wonderful opportunities for social interaction.   Preliminary plans are underway to repeat the event in late January 2016.  In the interim, we anticipate that a number of more detailed reports will be submitted for publication, and some exciting nascent projects will continue to grow.
If you want to contribute to the next ISARIC Newsletter, please contact Kajsa by email: kajsa-stina.longuere@ndm.ox.ac.uk
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